Fixed-Duration Glofitamab Elicits Early, Durable Complete Remissions in Relapsed/Refractory LBCL

Article

Michael Dickinson, MBBS, expands on data from a phase 2 dose-expansion study of glofitamab in heavily pretreated, highly refractory large B-cell lymphoma, explains the effect bispecific antibodies could have on treatment, and highlights other research efforts surrounding glofitamab-based therapies.

Michael Dickinson, MBBS

Michael Dickinson, MBBS

Fixed-duration glofitamab generated a notable objective response rate (ORR) and complete remission (CR) rate in patients with heavily pretreated, highly refractory large B-cell lymphoma (LBCL), according to data from a phase 2 trial (NCT03075696) presented at the 2022 ASCO Annual Meeting.

Along with high rates of response and CR, an encouraging 12-month CR rate pointed to the durability of fixed-duration glofitamab in highly pretreated patients with LBCL, said lead author Michael Dickinson, MBBS.

At a median follow-up of 12.6 months (range, 0-22), evaluable patients treated with glofitamab (n = 155) achieved an ORR of 51.6% (95% CI, 43.5%-59.7%) with a CR rate of 39.4% (95% CI, 31.6%-47.5%). The median time to first CR was 42 days (95% CI, 42-44).

Additionally, the median duration of CR (DOCR) was not estimable (NE; 95% CI, 16.8 months–NE). The 12-month DOCR rate was 77.6% (95% CI, 64.3%-90.8%).

“Glofitamab is a highly active treatment for all patients with relapsed and refractory LBCL after 2 prior lines of therapy,” Dickinson said. “It’s deliverable, its safety profile is excellent, and only 3.2% of patients stopped treatment because of a [treatment-related] adverse effect.”

In an interview with OncLive®, Dickinson, the lead of the Aggressive Lymphoma Disease Group at the Peter MacCallum Cancer Centre at Royal Melbourne Hospital and The University of Melbourne, expanded on the data from the phase 2 dose-escalation study. He went on to explain the effect bispecific antibodies could have on treatment for patients with relapsed/refractory B-cell lymphomas and highlighted other research efforts surrounding glofitamab-based therapies.

OncLive®: What was the rationale for investigating glofitamab in relapsed/refractory LBCL?

Dickinson: At the 2022 ASCO Annual Meeting, we presented the results of pivotal data for glofitamab, a CD20/CD3 bispecific antibody. [The] phase 1 study established the dose, and we presented the pivotal data of the application of that drug in LBCL [in phase 2 of the trial]. This includes diffuse large B-cell lymphoma not otherwise specified, high-grade B-cell lymphoma, transformed lymphoma, and primary mediastinal B-cell lymphoma.

Glofitamab is a distinct bispecific antibody because it has a 2:1 structure, which gives it potency in the setting [patients have received] other anti-CD20 antibodies. This is important because many of these patients will already have had drugs such as rituximab [Rituxan] and obinutuzumab [Gazyva]. [Glofitamab] is also unique because we use a single dose of obinutuzumab as cytokine release syndrome prophylaxis, and it’s unique against the other bispecific antibodies because we use it for a fixed duration.

Could you elaborate on the fixed-duration dosing used for glofitamab in this study?

After a process of stepping up the dose at 2.5 mg and 10 mg, we reached the target dose of 30 mg. From then on, we gave 30 mg once every 3 weeks for 12 cycles. This was a fixed-course [treatment and it was not continued in perpetuity]. The data presented at the 2022 ASCO Annual Meeting revealed data on this approach when it is applied to these aggressive lymphoma subsets.

What were the key efficacy findings presented at the 2022 ASCO Annual Meeting?

What we found was a CR rate of 39.4%. CR is particularly important in aggressive lymphomas because these are curable diseases, but there must be a CR to achieve cure. The vast majority of those CRs were retained at 12 months, as [77.6%] of patients [who achieved a CR] retained a CR at 12 months.

We know from other settings that if you achieve [a CR with a duration of at least 12 months], relapse is uncommon after that time point. This is an early sign that glofitamab at this dose in this population can achieve durable CRs.

Were there any surprises when evaluating the dataset?

The main highlight was the CR rate, seeing that we could get 39.4% of patients into a CR. Something that we learned through the phase 1 study, which may still be a surprise to other people, is how quickly those CRs can be achieved. We saw that happen at the first response assessment in 8 out of 10 patients who responded. At 42 days, these patients were in CR.

The other special thing about these data is that this is a treatment that is off the shelf. If a patient has relapsed aggressive lymphoma, they need to be treated quickly, so the ability to take a drug off the shelf and deliver remissions that [are comparable] to what can be achieved with products such as CAR T-cell therapy is impressive.

I’ve been involved in the development of this agent for years and had hopes from what I had seen in my clinic, because I have patients who I have followed out beyond 3 years and into their fourth year since having this drug at much lower doses. They’ve had bad refractory disease, achieved a CR, and retained it. This has been the first time that we've been able to show that in a large population of 155 patients.

How could fixed-duration glofitamab potentially fit into the treatment landscape in the future?

We know that the landscape is opening up in aggressive lymphoma. It is an exciting time to be treating these diseases. Previously, we had only high-dose chemotherapy and autologous stem cell transplant [ASCT]. Based on years of data, [those options] only cured a minority of patients who relapsed. Moreover, [patients who] relapsed after an ASCT had no great treatment options until some of the recent drug and CAR T-cell therapy approvals.

The population treated in this trial was a broad population. It had a good range of age, [and it included patients who were] post-ASCT and non–post-ASCT. We also included patients who had [prior] CAR T-cell therapy. A third of the population that we recruited had been exposed to CAR T cells, and they had [a similar] CR rate as the overall group [at 35%]. I see this as being a drug that can be taken off the shelf by oncologists and hematologists for any patient with relapsed LBCL in the third line or beyond, [irrespective of] whether patients had [prior] CAR T-cell therapy.

We hope we will be able to reach for this drug one day, and that’s where I see it being placed. [It could] be an option amongst what is a growing range of options, and we know that individual patients’ circumstances may dictate whether CAR T-cell therapy is feasible. We know that CAR T-cell therapy is not uniformly available to all patients around the world. Different regions have different needs, so I can see glofitamab fitting into that space.

Many patients don’t want to [travel to] the CAR T-cell therapy center. They want to stick with their own doctor, or they have personal medical reasons why it may not be possible to apply cellular therapy. Bispecific antibodies in general and glofitamab [in particular] will earn a place in that space with time.

What are the next steps for researching glofitamab across various malignancies?

There is a broad program that is being developed to look at how bispecific antibodies can be best applied and whether we can improve further on these response rates through rational combinations. We know that this drug is being looked at in earlier lines of therapy, going into the second line, and there are studies underway looking at it in combination with chemotherapy. There is already some data on if it can be combined safely with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone]. There may be a future where this could be brought to the frontline.

In Australia, I’m doing a clinical trial currently running at 13 sites looking at the combination of this drug with R-CHOP and R-CHP [rituximab, cyclophosphamide, doxorubicin, and prednisone] plus polatuzumab vedotin-piiq [Polivy] to see if we can address the needs of our ultra–high-risk patients with LBCL.

There is a lot of potential for [bispecific antibodies]. We are seeing some data in other histologies such as mantle cell lymphoma—data with glofitamab presented at the 2021 ASH Annual Meeting that showed that it’s a highly active treatment, even in patients who have refractory disease after BTK inhibitors. I want to see more of that data emerge and understand that better. However, drugs such as glofitamab can apply across a range of histologies, and in LBCL, [it could have a role] in earlier treatment lines and potentially in rational combinations.

How could the use of glofitamab affect the standard of care moving forward?

In the real world, when you apply this in the clinic, it’s a very applicable treatment. It’s straightforward to give, and the patients’ experience with it is very positive. They achieve remissions rapidly, and they stay on therapy. [Importantly], you can offer patients a horizon for that therapy, and you can have every expectation that those responses will be retained, which is exciting.

Reference

Dickinson M, Carlo-Stella C, Morschhauser F, et al. Glofitamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and ≥ 2 prior therapies: Pivotal phase II expansion results. J Clin Oncol. 2022;40(suppl 16):7500. doi:10.1200/JCO.2022.40.16_suppl.7500.

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